1,3,3,4,4-pentasubstituted pyrrolidines

ABSTRACT

Novel 1,3,3,4,4-pentasubstituted pyrrolidines having pharmacological activity.

Unlted States Patent [151 3,674,806 Bluhm et al. July 4, 1972 [54]l,3,3,4,4-PENTASUBSTITUTED 3,236,859 2/l966 Wollweber et al ..260/326.85

PYRROLIDINES 3,020,288 2/1962 Wragg et al ..260/326.8

[72] Inventors: Herbert J. Bluhm; Eugene R. Fluck, both OTHERPUBLICATIONS wmsmmsale Boehringer et al., Chem Abstracts, Vol. 58, pag12, 5 1 7+ e, [73] Assignce: R, J. Reynolds Tobacco Company, Win- June1964 Abstracting British Patent 915,456 dated Jan. 16,

ston-Salem, NC, 1963 Burger, Medicinal Chemistry, Second Edition,ln'terscience, 30, 1969 page 497, 1960 RS 403 B8 1960 c.7 [21] Appl.No.: 820,620

, Primary ExaminerAlan L. Rotman Attorney-Pendleton, Neuman, Williams &Anderson [52] US. Cl ..260/326.8, 260/296 R, 260/3265 N,

260/3265 M, 260/326.85, 424/263, 424/274 [57] ABSTRACT [51] Int. Cl...C07d 27/02 58 Fieldol'Search ..260/326.8,326.85,296R Novel 3, AA-ppyrrolidines having P macological activity. f [56] Re erences Cited 5Claims, N0 Drawings UNITED STATES PATENTS Villani et al. ..260/326.8

Bi i R2 FormulaI wherein R and R are alkyl, aryl, alkaryl or aralkylgroups containing not more than carbon atoms. These groups may pyridyl,pyridylmethyl or cycloalkyl containing not more than 12 carbon atoms,These groups may contain additional substituents such as halogen, nitro,alkoxy and the like. Representative groups include ethyl, butyl,dodecyl, diethyl-amino, pnitrophenyl, o-tolyl, p-ethoxyphenyl,p-hydroxyphenyl, 2,4- dichlorophenyl, 2,4-dimethylphenyl, p-biphenylyl,6-butoxy- 3-pyridyl, 4-methyl-2-pyridyl, cyclopropyl, cyclopentyl andthe like.

The novel compounds of this invention are prepared from iminescontaining an allylic hydrogen which, by oxidative coupling, yieldssuccinaldimines. Alternatively, said succinaldimines can be prepared byoxidative coupling of the ap propriate aldehyde followed by treatmentwith an appropriate amine. The succinaldimines are then reduced withconcommitant cyclization to form the compounds of this invention. Bis(l,l-dialkylhydrazones) prepared from the succinaldehyde and appropriatehydrazine can also be reduced to give the correspondingl-(dialkylamino)pyrrolidine.

The oxidative coupling of imines containing an allylic hydrogen to formsuccinaldimines is disclosed in copending application Ser. No. 759,750filed Sept. 13, 1968, now abandoned by John Charles Leffingwell, whichapplication is a continuation-in-part of a prior application, Ser. No.595,001 filed Nov. 17, 1966, now abandoned. Patent application Ser. No.27,173 filed Apr. 9, 1970 is in turn a continuation-in-part of said Ser.No. 759,750. Starting with a monomeric irnine, the

synthesis of the present compounds can be illustrated as follows, usingmanganese dioxide to achieve the coupling:

Oxidative coupling of an aldehyde to form a succinaldehyde is disclosedin the copending application Ser. No. 595,004, now abandoned, filed Nov.17, 1966 by John Charles Leflingwell. Application Ser. No. 595,004 wasreplaced by Ser. No. 820,629, on which application U.S. Pat. No.3,609,193 issued Sept. 28, i971. The coupled aldehyde can then bereacted with an appropriate amine to form succinaldimines which are thenreduced with concommitant cyclization to yield the desired products.Starting with an aldehyde the synthesis of the present compounds can beillustrated as follows:

Hydrogenation (reduction) of the intermediate succinaldimine can becarried out at ambient temperatures in the presence of platinum,palladium, rhodium or ruthenium on carbon, or Raney nickel utilizinghydrogen pressures of two or three atmospheres. It is preferred toemploy a solvent for the hydrogenation such as glacial acetic acid,ethanol containing small quantities of acetic acid or ethyl ethercontaining small quantifies of acetic acid. Reduction of thesuccinaldimines can also be accomplished using, for example, an excessamount of aqueous fon'nic acid or sodium borohydride in ethanol.

Hydrogenation of bis( l,l-dialkylhydrazones) with structures analogousto succinaldimines result in formation of pyrrolidines of the inventionwhen glacial acetic acid is used as the reaction medium.

The following examples illustrate preparation of the novel compounds ofthe present invention. All temperatures are given in degrees Centigrade.

EXAMPLE 1 Preparation of l-Ethyl-3,3,4,4-tetramethylpyrrolidine To acooled, stirred 90 gram (0.46 mole) sample of N,N-diethyltetramethylsuccinaldimine were added 95 grams (2.0 moles) of 88percent formic acid over a three hour period. Stirring was continued foran additional 2 hours at room temperature before the addition of excesspercent aqueous sodium hydroxide. The product mixture was extracted withtwo l00milliliter portions of ether, the combined extracts were washedwith three 20-milliliter portions of water, and the ether solution wasdried over anhydrous sodium sulfate. Removal of the ether anddistillation of the crude product gave 46 grams (65 percent) ofl-ethyl-3,3,4,4-tetramethylpyrrolidine as a colorless liquid, boilingpoint lO0-l05/ 100 millimeters of mercury. Conversion to thehydrochloride salt was carried out by treatment with hydrogen chloridein ether to EXANIPLE II In a manner similar to that of Example I,N,N'-dibenzyltetramethylsuccinaldimine was converted tol-benzyl-3,3,4,4-

tetramethylpyrrolidine, boiling point 79-82/0.5 millimeters of mercury(hydrochloride salt, melting point 1 7 8-l EXAMPLE Ill Preparation ofl-lsopropyl'3,3,4,4-ten-amethylpyrrolidine To a mixture of 325 grams(3.7 moles) of manganese dioxide in 300 milliliters of hexane was added,with stirring, 193 grams (l.7 moles) of N-isobutylideneisopropylamine.The resulting mixture was stirred at reflux temperature for 20 hours atwhich time the solids were removed by suction filtration using a frittedglass funnel of medium porosity. The solids were washed with 400milliliters of ether to remove any adhering product. Removal of thesolvents from the combined filtrates and distillation of the residualoil afforded grams (79 percent) ofN,N'-diisopropyltetramethylsuccinaldimine as a colorless liquid, boilingpoint l0l-l06/l 1.0 millimeters of mercury.

To 67.2 grams (0.3 mole) of N,N-diisopropyltetramethylsuccinaldimine wasadded, with cooling and stirring, 46 grams 1.0 mole) of 97 percentformic acid over a 30-minute period. Stirring was continued for 17 hoursand the product was isolated in a manner analogous to Example I. A yieldof 46.3 grams (91 percent) of l-isopropyl-3,3,4,4-tetramethylpyrrolidineas a colorless liquid, boiling point 1 l2-4/90 millimeters of mercury,was obtained. The pyrrolidine was converted to1-isopropyl-3,3,4,4-tetramethylpyrrolidine hydrochloride in 82 percentyield by treatment with hydrogen chloride in ether. The salt wasrecrystallized from an isopropanolethanol-ether mixture to give whitecrystals, melting point l95205.

EXAMPLE IV Preparation of l-n-Butyl-3 ,3,4,4-tetramethylpyrrolidine Amixture consisting of 12.6 grams (0.05 mole)N,N'-di-nbutyl-2,2,3,3-tetramethylsuccinaldimine, 25 milliliters glacialacetic acid, and 0.4 gram 5 percent platinum on carbon was hydrogenatedat 50 p.s.i.g. for 15 hours. The mixture was then diluted with 100milliliters of ether and the catalyst was removed by filtration througha fritted glass funnel. Excess 40 percent aqueous sodium hydroxide wasadded to the filtrate and the ether layer was separated and washed withwater before drying over anhydrous sodium sulfate. Removal of thesolvent and distillation of the crude product yielded 7.0 grams (77percent) of l-n-butyl-3,3,4,4-tetramethylpyrrolidine as a colorless oil,boiling point 80-l/7.5 millimeters of mercury. Similar hydrogenations inacetic acid were carried out with the following catalysts to give theindicated yields of crude ln-butyl-3,3,4,4-tetramethylpyrrolidine: 5percent palladium on charcoal (92 percent); 5 percent rhodium on carbon(95 percent); 5 percent ruthenium on carbon (48 percent); and Raneynickel (52 percent).

Conversion of the above pyrrolidine to the hydrochloride salt (in ether)and recrystallization from isopropanol-ether was effected in 82 percentyield to give l-n-butyl-3,3,4,4- tetramethylpyrrolidine hydrochloride aswhite crystals, melting point l90-2l0 (dec.).

EXAMPLE V In a manner similar to that of Example IV, the followingpyrrolidines were prepared from the corresponding succinaldimines:1-cyc1ohexyl-3,3,4,4-tetramethylpyrrolidine (boiling point 98-l02/2.2millimeters of mercury), l-isobutyl-3,4-din-butyl-3,4-diethylpyrrolidine(boiling point ll8l22/0.25 millimeters of mercury),l-n-butyl-3,4-dimethyl-3,4-di(4- isopropylbenzyl)pyrrolidine (boilingpoint 201-206/0.05 millimeters of mercury),1-(3-pyridylmethyl)-3,3,4,4-tetramethylpyrrolidine (boiling pointlOl02/0.5 millimeters of mercury), andl-isobutyl-3,3,4,4-tetramethylpyrrolidine (boiling point 78-79/ l 5.0millimeters of mercury.

EXAMPLE VI Preparation of l-n-Butyl-3,4-dimethyl-3,4-diphenylpyrrolidine Coupling of N-( 2-phenylpropylidene)-n-butylamine(40 grams) via manganese dioxide was carried out in a manner similar tothat described in Example III except that the crude product was notdistilled but used directly in the hydrogenation step. The crude productwas placed in 100 milliliters of glacial acetic acid with 2 grams ofpercent platinum on carbon and hydrogenated at 50 p.s.i.g. and roomtemperature for 19 hours. The product was isolated as described inExample IV and was distilled under reduced pressure to give 23 grams (68percent) of l-n-butyI-3,4-dimethyl-3,4-diphenylpyrrolidine as a yellowoil, boiling point 155-16010.2 millimeters of mercury.

Using the procedure described above, the following compounds areprepared from the corresponding aldimines: 1-

isopropyl-3 ,4-dibutyl-3 ,4-diamylpyrrolidine, l-isopropyl- 3 ,4-dimethyl-3 ,4-di( 2-nitrobutyl )pyrrolidine, l-ethyl- 3 ,4- dimethyl-3,4-di(4-methoxyphenyl)pyrrolidine, l-butyl-3,4- dimethyl-3,4-di(4-bromophenyl)pyrrolidine, l-ethyl-3 ,4-dimethyl3,4-di(4-isopropy1phenyl)pyrrolidine, andlisopropyl-3,3,4,4-tetra-phenylpyrrolidine.

EXAMPLE VII Preparation of l-n-Dodecyl-3 ,3,4,4-tetramethylpyrrolidineTo a mixture of 20 grams (0.14 mole) of tetramethylsuccinaldehyde in 75milliliters of ether was added 55 grams (0.3 mole) of dodecylamine. Theresulting mixture was stirred at room temperature for 1 hour and wasthen dried over sodium hydroxide overnight. Isolation of the crudeproduct gave 71 grams of yellow oil. Hydrogenation of this oil wascarried out in 120 milliliters of glacial acetic acid containing 2 gramsof 5 percent platinum on carbon. The hydrogenation was allowed toproceed for 22 hours at room temperature and 50 p.s.i.g. Isolation ofthe product in a manner analogous to that described in Example IV abovegave 66 grams of crude material. Distillation of this material underreduced pressure gave 27.5 grams (67 percent) of l-n-dodecyl-3,3,4,4-tetramethylpyrrolidine as a colorless oil, boiling point l25-6 /O.1millimeter of mercury. Conversion to the hydrochloride salt by passinghydrogen chloride gas into a hexane solution of the pyrrolidine gave an86 percent yield of l-n-dodecyl- 3,3,4,4-tetramethylpyrrolidinehydrochloride as colorless leaflets, melting point l74-l75.5 (from ethylacetate).

EXAMPLE VIII In a manner analogous to that of Example VII, the followingpyrrolidines were prepared from tetramethylsuccinaldehyde and theappropriate amines: 1-( 2-hydroxyethyl)- 3,3,4,4- tetramethylpyrrolidine(boiling point 96/5.0 millimeters of mercury) andl-(2-phenylethyl)-3,3,4,4-tetramethylpyrrolidine (boiling point l33l37/2.0 millimeters of mercury).

EXAMPLE IX Preparation of l-(Dimethylamino)-3,3,4,4-tetrarnethylpyrrolidine A mixture of 13 grams (0.09 mole)tetramethylsuccinaldehyde, 12 grams (0.2 mole) l,l-dimethylhydrazine,and a few drops of glacial acetic acid was warmed gently on a steam bathfor 1 hour. The mixture was cooled and 5 grams of crude product wascollected by suction filtration. Treatment of the filtrate with anadditional 10 grams of l,l-dimthylhydrazine plus a small amount of 88percent formic acid resulted in the isolation of an additional 6 gramsof crude product. Recrystallization of the crude product from ether,using activated charcoal, gave 9.0 grams (44 percent) oftetramethylsuccinaldehyde bis( l,l-dimethyl-hydrazone) as colorlesscrystals, melting point 9 l-93.

A solution of 8.0 grams (0.0375 mole) of tetramethylsuccinaldehydebis(],l-dimethylhydrazone) in 50 milliliters of glacial acetic acid washydrogenated over 0.8 gram of 5 percent platinum on carbon at 50p.s.i.g. for 40 hours. The mixture was diluted with ether and thecatalyst was removed by filtration. Excess 40 percent sodium hdyroxidewas added to the filtrate, and the ether layer was separated and washedwith water before drying over anhydrous sodium sulfate. Removal of theether gave 4.5 grams of yellow oil and 1.35 grams (17 percent) ofrecovered dihydrazone. Distillation of the oil under reduced pressureyielded 3.95 grams (62 percent) of l-(dimethylamino)-3,3,4,4-tetramethylpyrrolidine as a colorless liquid,boiling point 87-89/22.0 millimeters of mercury.

Using the foregoing procedure, l-(diethylamino)-3,3,4,4-tetramethylpyrrolidine is prepared by substituting l,l-diethylhydrazinefor the l,l-dimethylhydrazine.

EXAMPLE X Preparation of l-Phenyl-3,3,4,4-tetramethylpyrrolidine Amixture of 7.1 grams (0.05 mole) of tetramethylsuccinaldehyde and 4.65grams (0.05 mole) of aniline was heated on a steam bath for '30 minutes.This mixture was then cooled and to it was added, with stirring, grams(0.19 mole) of 88 percent formic acid. The mixture was stirred at roomtemperature for 16 hours during which time a dark bluish-black color wasgenerated. A solution of 5 grams of sodium hydroxide in milliliters ofwater was added and the product was extracted with ether. Distillationof the crude product gave 4.3 grams (42 percent) ofl-phenyl-3,3,4,4-tetramethylpyrrolidine as a slightly yellow oil,boiling point 8285/0.l millimeter of mercury. This pyrrolidine wasconverted in 53% yield to the hydrochloride salt (using ether). Thel-phenyl-3,3,4,4- tetramethylpyrrolidine hydrochloride gave colorlesscrystals from ethanol-ether, melting point 85-l 10.

Utilizing the above method, the following compounds are prepared bysubstituting the appropriate amine for aniline: l-(2,4-dichlorophenyl)-3,3,4,4-tetramethylpyrrolidine, l-(p biphenylyl )-3,3 ,4,4-tetramethylpyrrolidene, l-( 6-butoxy-3- pyridyl )-3 ,3,4,4-tetramethylpyrrolidine, l-(2,4-dimethylphenyl)-3,3,4,4-tetramethylpyrrolidine, 1-(p-hydroxyphenyl)-3 ,3 ,4 ,4-tetramethylpyrrol idine, l-( 4-methyl-2-pyridyl 3 ,3,4,4-tetramethylpyrrolidine, l-(p-ethoxyphenyl )-3 ,3 ,4,4-tetramethylpyrrolidine, l-( o-tolyl )-3 ,3 ,4,4-tetramethylpyrrolidine,and l-(p-nitrophenyl)-3,3,4,4-tetramethylpyrrolidine.

Chemical compounds embraced by Formula I can be employed for loweringthe level of cholesterol in the blood serum. Atherosclerosis is asignificant form of cardiovascular disease and higher levels ofcholesterol are observed in atherosclerosis patients than in normalpersons. Control of blood cholesterol levels is felt to be important inthe treatment and prevention of atherosclerosis.

To illustrate the ability of compounds embraced by this invention forlowering blood cholesterol levels, comparisons were made with acommercially available nonsteroidal compound which is presently employedfor lowering serum cholesterol levels in humans. This compound is ethyla-(4- chlorophenoxy)isobutyrate (CPIB). The test is carried out asfollows:

Five male rats weighing 150-200 grams were used in each test group. In atypical test, the test compounds were administered at appropriate dosesorally for five consecutive days. A control group and a standard groupwere run each time. The control group received only the solvent whichwas used to suspend the test compounds and the standard group receivedCPIB at 200 mg/kg. The animals were fasted overnight on the fourth nightof the experiment, and on the fifth day the animals were bled viacardiac puncture under ether anesthesia two hours after the final drugadministration. The sera were analyzed for cholesterol. The percentagechange in serum cholesterol caused by the test compounds and by CPIB wascalculated as follows:

Serum cholesterol of control-serum cholesterol of test Serum cholesterolof control 1 r. 199. The results were as follows:

Percent Reduction in Compound Dose Cholesterol Level Product of ExampleX (PTMP) 300 mg/kg 31% Product of Example X (PTMP) 150 mg/kg 22% Productof Example X (PTMP) 75 mg/kg 2.5% CPlB 200 mg/kg 23% Following the testprocedure above outlined, CPIB was administered at 200 mg/kg andl-phenyl-3,3,4,4-tetramethylpyrrolidine hydrochloride (PTMP) at 300mg/kg for 32 consecutive days. P'IMP lowered serum cholesterol by 42.5percent whereas CPIB lowered it by 21 percent. The sera were alsoanalyzed for glucose, urea nitrogen, calcium, bilirubin, total protein,alkaline phosphatase, serum glutamic-oxaloacetic transaminase, serumglutamic-pyruvic transaminase, and the livers were processedhistologically. There was no apparent toxicity judging by appearance ofthe animals, the blood chemistries and microscopic examination of theliver tissue.

The following test results illustrate hypocholesterolemic responses inrats by different routes of administration.

The toxicity of the above compounds (LD in rats) is approximately 1,500mg/kg for CPIB and greater than 1,500 mg/kg for PT MP.

As is apparent from the foregoing, the novel pyrrolidine compounds ofthe invention can be readily converted to the salt form thereof. Forexample, acid addition salts such as the hydrochloride, sulfate,phosphate, acetate, propionate, tartrate, mucate, maleate and gluconatesalts can be prepared by conventional means by reacting the free baseform of the new compounds with an appropriate acid. Quaternary ammoniumsalts are prepared by reacting a pyrrolidine with an appropriatecompound such as methyl chloride, methyl bromide, allyl chloride, benzylchloride and the like.

Those modifications and equivalents which fall within the spirit of theinvention are to be considered a part thereof.

WE CLAIM:

1. A compound selected from the group con-sisting of:

a a compound of the formula l Ra wherein R, and R are alkyl groupscontaining from one to four carbon atoms and R, is phenyl or alkylphenylcontaining not more than nine carbon atoms with or without substituentsselected from halogen, nitro and lower alkoxy,

b. a therapeutically acceptable salt of a compound defined in (a). 2. Acompound of the formula wherein R, and R are methyl and R is phenyl.

3. A compound in accordance with claim 2 in the form of itshydrochloride salt.

4. A compound in accordance with claim 1 wherein R, and R are methylgroups and R is benzyl.

5..A compound in accordance with claim 1 wherein R, and R are methylgroups and R is Z-phenylethyl.

V UNITED STATES PATENT OFFICE CERTIFICATE OF PatentlNo. 3, 674, 806Dated JlllV 4', 1972 Inventor(s) Herbert J.- Bluhm and Eugene R. FluckIt is certified that error appears inthe above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 2, line 50, 'tetremethyl-pyrrolidine" should be v vtetramethylpyrrolidine Column 3, line 72 l55-l60"10.2" should be'l55l60/ O.2

Column 4, line 6; "tetra-phenylpyrrolidine" should be' Itetraphenylpyrrolidine line 57,- "dimethyl-hydrazone" should bedimethylhydrazone Column 5, line 23-, "tetramethylpyrrolidene should bei tetramethylpyrrolidine lines 60-64 should read as follows:

SERUM CHOLESTEROL OF CONTROL SERUM CHOLESTEROL OF TEST X 100 1 SerumCholestero'l of Control Column 6, in the table, the numbers appearingafter "PTMZP" and "GPIB" should be under the column headed 'Dose" line44, "a", first occurrence, sh ouldbe (a) v line57, "b..' 'mshould be (b)I Signed and sealed this 12th day of December 1972.

(SEAL) Attest:

EDWARD M.FUETCHER,JR. ROBERT GOTTSCHALK Attesting Officer I Commissionerof Patents FORM PO-IOSO (10-69) I uscomwoc scan-baa i U. 5 GOVERNMENTPRINT NG OFFICI: llll O-liO-Sll

2. A compound of the formula
 3. A compound in accordance with claim 2 inthe form of its hydrochloride salt.
 4. A compound in accordance withclaim 1 wherein R1 and R2 are methyl groups and R3 is benzyl.
 5. Acompound in accordance with claim 1 wherein R1 and R2 are methyl groupsand R3 is 2-phenylethyl.